Sixty-four homozygous beta-thalassemia patients comprising 40 patients with beta-thalassemia major and 24 patients with beta-thalassemia intermedia were investigated for the nature of their beta-thalassemia mutations, associated alpha-thalassemia, and XmnI polymorphism in the gamma gene which are known to affect the clinical course of the disease. This study was undertaken to look for the contribution of these associated factors in reducing the clinical severity of homozygous beta-thalassemia from a severe disease to a beta-thalassemia intermedia phenotype. Clinical severity of these patients was assessed by the degree of transfusion dependency and the age at which the patient presented with symptoms. Globin chain synthetic ratio was taken as the biochemical pointer of severity of the disease. Eleven different beta-thalassemia mutations were encountered among 128 beta-thalassemia chromosomes. It was observed that the nature of the beta-thalassemia mutations was not very different between the beta-thalassemia major and beta-thalassemia intermedia groups in our patients, but co-inheritance of one or more alpha-globin gene deletions (-alpha(3.7)) and the presence of the XmnI polymorphism were associated with lesser severity of the disease in Indians.